In the US, sepsis is a major cause of morbidity and mortality occurring in around 700,000 individuals per year. Respiratory dysfunction in individuals with sepsis is common. However, lung function in these patients can often be adequately supported, and mortality most often results from unresolved sepsis or multiple organ failure. Previous studies have focused on how systemic manifestations of sepsis affect the lung. Here, we will examine how the lung can be detrimental to the heart during sepsis. Macrophage migration inhibitory factor (MIF), an important mediator in sepsis, has been shown recently to be a cardiac depressant factor, and to play a critical role in the mortality associated with sepsis. Our studies suggest that MIF accumulates within the lung during sepsis and is released into the pulmonary circulation contemporaneous with the onset of cardiac dysfunction. Therefore, we hypothesize that during sepsis, the lung acts as an inflammatory organ, releasing MIF into the alveolae and the pulmonary circulation in a time dependent manner. MIF released from the lung passes directly into the coronary circulation where it interacts with the cardiac myocytes causing cardiac dysfunction. To address this hypothesis, the proposal has three specific aims: 1) To identify the cellular source of MIF in the lung, and determine the timing of its alveolar accumulation, and release into the pulmonary circulation during sepsis; 2) To identify mechanisms involved in lung-derived, MIF-dependent, cardiac myocyte cell dysfunction; and 3) To determine whether specific inhibition of MIF during sepsis protects against cardiac dysfunction by reducing cardiac myocyte activation. Septic peritonitis and recombinant MIF, in normal animals and in animals in which the MIF gene has been deleted (either totally, or in specific cell types) will be used to examine the MIF mediated interactions between the lung and heart during sepsis. Using our specific MIF inhibitor to minimize MIF activity, or by cell blockade or depletion of cells involved in the generation of lung-derived MIF, the benefit of reducing the MIF burden on cardiac myocytes during sepsis will be determined. Thus we expect that the study will identify the role and mechanisms involved in pulmonary-MIF derived cardiac dysfunction during sepsis and suggest specific strategies to inhibit its production and release from the lung. [unreadable] [unreadable] [unreadable]